Many important medicinal compounds contain achiral aromatic groups with appended chiral substituents. One of the most powerful methods for the construction of products comprising aromatic ring systems (benzenes, naphthalenes, etc.) is cyclopentadienyl cobalt (CpCo) transition metal mediated [2+2+2] cycloaddition of first, second and third reactant alkynes (referred to herein as the "cyclotrimerization" of alkynes). Vollhardt has used this reaction in the eloquent syntheses of many biologically active compounds. (Vollhardt (1984) Angew. Chem. Int. Ed. Engl. 23:539, and references therein). It should be noted that transition metal mediated [2+2+2] cyclotrimerization is not limited to alkyne reactants and that non-aromatic six membered ring products can be assembled by combining alkyne and alkene reactants. Additionally, heterocyclic aromatic ring systems, such as pyridines, can be synthesized by cyclotrimerization of alkynes and nitrites.
The cyclotrimerization of alkynes to aromatic compounds is, therefore, of fundamental importance in the area of synthetic chemistry and considerable effort has gone into the development of methods to perform this reaction. (See, e.g., Vollhardt (1984) Angew. Chem. Int. Ed. Engl. 23:539, and references therein; Collman et al. (1987) in Principles and Applications of Organotransition Metal Chemistry, University Science Books: Mill Valley, Calif. pp. 870-879; Schore (1988) Chem. Rev. 88:1081).
The thermal cyclotrimerization of acetylene to benzene was first reported by Berthelot in 1866. (Berthelot (1866) C.R. Acad. Sci. 62:905). The reaction required elevated temperatures (400.degree. C.) and gave a mixture of products. In 1949, Reppe et al. described a transition metal mediated version of this transformation, in which nickel was employed as the catalyst. The major product of this reaction, however, was cyclooctatetraene not benzene. (Reppe et al. (1948) Justus Liebigs Ann. Chem. 560:1). Several transition metals have now been identified as active catalysts in the [2+2+2] cyclotrimerization of alkynes to aromatic compounds, some of which are described below.
A number of studies have been undertaken using Ziegler type catalysts, such as TiCl.sub.4 /AlEt.sub.3, to perform [2+2+2] cyclotrimerizations. The reactions are carried out in an inert solvent, such as benzene, or absolute ethanol at refluxing temperatures. Generally, only alkyl or phenyl substituents are allowed and the reactions typically produce polymeric side products. (Parshall (1980) in Homogeneous Catalysis; ch. 11, Wiley: New York; Franzus et al. (1959) J. Am. Chem. Soc. 81:1514; Meriwether et al. (1961) J. Org. Chem. 26:5155-5163; Lutz (1961) J. Am. Chem. Soc. 83:2551; Lachmann et al. (1987) J. Molecular Catalysis 42:151; Du Plessis et al. (1991) J. Molecular Catalysis 42 64:269). Additionally, Ziegler type catalysts will not survive aqueous conditions.
Several rhodium catalysts, for example catalysts 1a-c and 2a-c, demonstrate the ability to cyclotrimerize alkynes. (See e.g., Collman et al. (1968) Inorg. Chem. 7:1298; Wakatsuki and Yamazaki (1974) J. Organomet. Chem. 50:393; Cash et al. (1973) J. Organomet. Chem. 50:277; Borrini et al. (1985) J. Molecular Catalysis 30:181. See also, Grigg et al. (1988) J. Chem. Soc. Perkin Trans. I 1357-1364, for a discussion of Wilkinson's catalyst [(PPh.sub.3 RhCl)]). These reactions are run in anhydrous solvents, such as, absolute ethanol and produce many catalytically inactive metal complexes, resulting in low catalyst turnovers. Additionally, rhodium is too expensive to be considered for large scale synthetic use. ##STR1##
As mentioned above, the use of nickel catalysts in the cyclotrimerization of alkynes was first explored in 1948, resulting mostly in cyclooctatetraene formation. (Reppe et al. (1948) Justus Liebigs Ann. Chem. 560:1). In more recent studies Ni catalysts 3a-c exhibited good selectivity for cyclotrimerization product, with the formation of no unwanted cyclooctatetraene side products. (Rosenthal and Schulz (1987) J. Organomet. Chem. 321:103). ##STR2##
The use of trialkyl phosphines in conjunction with nickel catalyst 4, also gives good yields of cyclic trimer with some dimer formation, but no cyclooctatetraene (Table 1). In the case where no trialkyl phosphine ligands were present, dimer was reported to be the major product with some cyclooctatetraene formation. These results indicate the production of a phosphine-nickel catalyst in situ, followed by cyclotrimerization. The electron donating P(Bu).sub.3 ligand demonstrated the best selectivity to form cyclic trimers. These reactions are run in dry inert solvents at elevated temperatures.
TABLE 1 ##STR3## Trialkyl Phosphine Co-catalyst (2:1) Trimer Cycloctatetraene Dimer % Ratio % % RC.tbd.C--CH.dbd.CHR none 1.1 9 66.3 P(Ph).sub.3 80.8 0 17 P(Bu).sub.3 83 0 13 P(Cy).sub.3 75 0 19
By far the most studied and useful cyclotrimerization catalysts have been of the .eta..sup.5 -cyclopentadienyl cobalt (CpCo) family. In 1967, Yamazaki and Hagihara isolated the first cobalt cyclopentadiene triphenylphosphine complex (CpCoP(Ph).sub.3), which when treated with a stoichiometric amount of diphenylacetylene in refluxing toluene produced hexaphenylbenzene in 8% yield after one hour. (Yamazaki and Hagihara (1967) J. Organomet. Chem. 7:22). Cobalt cyclopentadiene dicarbonyl (CpCo(CO).sub.2) (5), a commercially available catalyst, reacts catalytically with bis-alkynes (6) in refluxing n-octane to form several bicyclic systems (7), including benzocyclobutenes (n=2) in 45% yield. (Vollhardt and Bergman (1974) J. Am. Chem. Soc 96:4996). ##STR4##
Vollhardt was the first to realize the potential of cobalt catalyzed cyclotrimerization. (Vollhardt and Bergman (1974) J. Am. Chem. Soc. 96:4996; Vollhardt (1984) Angew Chem. Int. Ed. Engl. 23:539). When it appeared that everything had been done in metal-mediated [2+2+2] cyclotrimerization, additional landmark reports appeared that expanded the repertoire of synthetic transformations. Recent examples that demonstrate the breadth of chemistry and concomitant diversity in structures that may be assembled by cobalt catalyzed cyclotrimeriztion include steroids (Funk and Vollhardt (1980) J. Am. Chem. Soc. 102:5253; Sternberg and Vollhardt (1984) J. Org. Chem. 49:1564; Hillard et al. (1983) Tetrahedron 37:905; Lecker et al. (1986) J. Am. Chem. Soc. 108:856), carbazoles (Grotjahn and Vollhardt (1986) J. Am. Chem. Soc. 108:2091; Boese et al. (1994) Synthesis 1374), stemodin (Germanas et al. (1991) J. Am. Chem. Soc. 113:4006), illudol (Johnson and Vollhardt (1991) J. Am. Chem. Soc. 113:381), phenylenes (Schmidt-Radde and Vollhardt (1992) J. Am. Chem. Soc. 114:9713), .gamma.-lycorane (Grotjahn and Vollhardt (1993) Synthesis 579) and the ergot alkaloids lysergic acid and lysergene (Saa et al. (1994) Synlett., 487). From conducting oligomers to important medicinal compounds, cyclotrimerization has had an enormous impact on the synthetic strategies that can be envisaged.
Until recently, water was considered to be detrimental to low valent organometallic transition metal catalysts, such as CpCo, due to their sensitivity to both oxygen and water, resulting in either oxidation of the metal or hydrolysis of the organometallic compound. (Parshall (1980) in Homogeneous Catalysis Wiley: New York). Water has been used as a media for a number of higher oxidation state organometallic-mediated transformations, including polymerization reactions (Novak and Grubbs (1988) J. Am. Chem. Soc. 110:7542-7543), asymmetric hydrogenation of alkynes using water-soluble rhodium complexes of sulfonated tertiary phosphines and water-soluble diphosphines (Toth and Hanson (1990) Tetrahedron: Asymmetry 1:895-912; Nagel and Kinzel (1986) Chem. Ber. 119:1731; Alario et al. (1986) J. Chem. Soc. Chem. Commun. 202-203; Amrani et al. (1989) Organometallics 8:542-547; Sinou (1987) Bull. Soc. Chim. Fr. 480) and asymmetric hydrogenation of imines (Bakos et al. (1989) Abstract of 5th OMCOS, Florence, Italy, PS1-36). These reactions exhibit increased selectivity in product distribution and increased activity of catalysts. In addition, the separation of organic products in aqueous solutions from the water soluble catalysts has enhanced product recovery and enabled the recovery and reuse of the catalyst. (Novak and Grubbs (1988) J. Am. Chem. Soc. 110:7542-7543; Toth and Hanson (1990) Tetrahedron: Asymmetry 1:895-912; Nagel and Kinzel (1986) Chem. Ber. 119:1731; Alario et al. (1986) J. Chem. Soc. Chem. Commun. 202-203; Amrani et al. (1989) Organometallics 8:542-547; Sinou (1987) Bull. Soc. Chim. Fr. 480). Thus, the use of aqueous media has significantly improved these catalytic systems.
Due to environmental and health concerns, and the costs associated with the use and disposal of organic solvents, there is a great deal of interest in developing reactions that can be performed in aqueous solutions. For all of these reasons it would, therefore, be desirable to be able to perform organometallic-mediated reactions involving low valent metals in aqueous solutions. In order to perform organometallic reactions in aqueous media, however, it is first necessary to prepare water soluble catalysts. To date there have been no reports of low valent transition metal catalysts useful for cyclotrimerization reactions that are stable and soluble in water.